KR20020092907A - Non-aromatic estrogenic steroids with a hydrocarbon substituent in position 11 - Google Patents

Abstract

The present invention discloses novel selective estrogen type compounds of steroid backbones having non-aromatic A-rings and hydroxyl groups free or capped at carbon number 3. Estrogen compounds satisfy Formula I:

Formula I

Where

R ¹ is H, (C ₁ -C ₃ ) alkyl or (C ₂ -C ₃ ) acyl;

R ² is H, α- (C ₁ -C ₄ ) alkyl, α- (C ₂ -C ₄ ) alkenyl or α- (C ₂ -C ₄ ) alkynyl;

R ³ is H or (C ₁ -C ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl or (C ₂ -C ₄ ) alkynyl at the 15 or 16 position of the steroid backbone, respectively;

R ⁴ is H or (C ₁ -C ₅ ) alkyl, (C ₂ -C ₅ ) alkenyl or (C ₂ -C ₅ ) alkynyl, each optionally substituted with halogen; Preferably ethynyl;

R ⁵ is H, (C ₁ -C ₃ ) alkyl or (C ₂ -C ₃ ) acyl;

R ⁶ is (C ₁ -C ₅ ) alkyl, (C ₂ -C ₅ ) alkenyl, (C ₂ -C ₅ ) alkynyl or (C optionally substituted with halogen or (C ₁ -C ₃ ) alkyloxy, respectively ₁ -C ₅ ) alkylidene;

Dotted lines indicate optional double bonds.

Description

NON-AROMATIC ESTROGENIC STEROIDS WITH A HYDROCARBON SUBSTITUENT IN POSITION 11}

Many estrogen compounds are known. For example, the guideline for estrogen compounds having a non-aromatic A ring and a hydroxyl group free or capped at carbon 3 is US Pat. No. 3,413,287. Other documents describing the estrogen or hormonal effects of non-aromatic steroids having 3-hydroxyl substituents and 4-5 double bonds include WO 94/18224, US Pat. No. 3,465,010, FR 2099385, US Pat. No. 3,652,606 and EP 145 493 and the like. Non-aromatic steroids with 3-keto substituents and 5-10 double bonds are disclosed in US Pat. No. 3,377,366 to Baran et al. Such compounds are generally disclosed as agents, among others, having an estrogen or antiestrogenic effect. Recently, attention has been focused on the discovery of two different types of estrogen receptors, labeled ERα and ERβ, in the field of drugs against estrogen receptors (ER). FEBS Letters 392 (1996) 49-53 and EP-A- 0 798 378). Because these receptors have different distributions in human tissues, finding compounds that have selective affinity for one of two classes is an important technological advance, and it is possible to treat estrogen deficiency-related diseases more selectively while lowering estrogen-related side effects. To be.

The present invention relates to the field of estrogen compounds of steroid backbones having non-aromatic A-rings and hydroxyl groups free or capped at carbon number 3. Estrogen compounds are generally recognized to be useful in the treatment of contraception and estrogen deficiency related diseases such as menopausal diseases and osteoporosis.

The present invention provides an estrogen that satisfies the following formula (I).

Where

R ¹ is H, (C ₁ -C ₃ ) alkyl or (C ₂ -C ₃ ) acyl;

R ² is H, α- (C ₁ -C ₄ ) alkyl, α- (C ₂ -C ₄ ) alkenyl or α- (C ₂ -C ₄ ) alkynyl;

R ³ is H or (C ₁ -C ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl or (C ₂ -C ₄ ) alkynyl at position 15 or 16 of the steroid skeleton, respectively;

R ⁴ is H or (C ₁ -C ₅ ) alkyl, (C ₂ -C ₅ ) alkenyl or (C ₂ -C ₅ ) alkynyl, each optionally substituted with halogen; Ethynyl is preferred;

R ⁵ is H, (C ₁ -C ₃ ) alkyl or (C ₂ -C ₃ ) acyl;

R ⁶ is (C ₁ -C ₅ ) alkyl, (C ₂ -C ₅ ) alkenyl, (C ₂ -C ₅ ) alkynyl or (C optionally substituted with halogen or (C ₁ -C ₃ ) alkyloxy, respectively ₁ -C ₅ ) alkylidene; Allyl is preferred; Preferred halogens for R ⁶ are fluorine and chlorine.

Dotted lines indicate optional double bonds. R ⁶ is a dashed line for R ⁶ alkylidene denotes a combination of more present in the alkylidene part, the combination of the two R ⁶ is an alkyl or alkenyl group R ⁶ in the atom 11 is a single bond.

These non-aromatic estradiol derivatives having substituents at position 11 of the steroid backbone have been found to possess selective affinity for the ERα-receptor.

The compounds of the present invention are suitable as improved estrogens in view of their use in estrogen related diseases such as postmenopausal diseases and osteoporosis. These compounds have been found to be useful for contraception and may also be suitable for the treatment or prevention of Alzheimer's disease, breast cancer, benign prostatic hyperplasia and cardiovascular disease. The compounds of the present invention are particularly suitable for treating and preventing estrogen deficiency related diseases while reducing estrogen related side effects.

The meanings of the terms herein are as follows:

(C ₁ -C ₅ ) alkyl is a branched, unbranched or cyclic alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, isopropyl, 2-methylcyclopropyl, butyl, sec-butyl, t-butyl, etc. ;

(C ₂ -C ₅ ) alkenyl is a branched, unbranched or cyclic alkenyl group having 2 to 5 carbon atoms, for example, ethenyl, 2-butenyl and the like.

(C ₂ -C ₅ ) alkynyl is a branched or unbranched alkynyl group having 2 to 5 carbon atoms, for example ethynyl and propynyl.

(C ₂ -C ₃ ) acyl is a group derived from an alkylcarboxylic acid having 2 to 3 carbon atoms and the alkyl moiety is as described above.

(C ₁ -C ₅ ) alkylidene is a branched, unbranched or cyclic alkylidene group having 1 to 5 carbon atoms, such as methylene and ethylidene.

Within the scope of the above-mentioned formula, the compound of the present invention preferably satisfies the following formula (II).

Where

R ¹ is H, (C ₁ -C ₃ ) alkyl or (C ₂ -C ₃ ) acyl;

R ² is H, α- (C ₁ -C ₄ ) alkyl, α- (C ₂ -C ₄ ) alkenyl or α- (C ₂ -C ₄ ) alkynyl;

R ³ is H or (C ₁ -C ₄ ) alkyl at position 16 of the steroid backbone;

R ⁴ is ethynyl;

R ⁵ is H, (C ₁ -C ₃ ) alkyl or (C ₂ -C ₃ ) acyl;

R ⁶ is (C ₁ -C ₅ ) alkyl, (C ₂ -C ₅ ) alkenyl, (C ₂ -C ₅ ) alkynyl, which may be substituted with chlorine or fluorine, respectively. When R ⁶ is (C ₁ -C ₂ ) alkyl, ethenyl or ethynyl, each optionally substituted with chlorine or fluorine, R ³ is preferably methyl at position 16 of the steroid backbone.

In Chemical Formula II,

R ¹ is H;

R ² is H;

R ³ is H or 16 α-methyl;

R ⁴ is ethynyl;

R ⁵ is H;

More preferred are steroids of the invention wherein R ⁶ is propenyl, allyl or butenyl.

The compounds of the present invention can generally be prepared by various methods known in the field of organic chemistry and in particular in the field of steroid chemistry. See, for example, Fried J. and Edwards JA, " Organic Reactions in Steroid Chemistry ", Vol I and Vol II, Van Nostrand Reinhold Company, New York, 1972; And C. Djerassi, “Steroid Reactions”, Holden-Day, Inc., San Francisco, 1963.

Synthesis of steroids with specific substituents at the C7 position is generally easy to remove via 7α induced steroids (crystallization or chromatography), for example through addition of an organometallic species conjugate to an appropriate 4,6-dien-3-one steroid. With small amounts of 7β steroids that can be produced). Several examples are known in the literature. The introduction of a substituent at the C11 position of the steroid backbone can be carried out in several ways. Conjugation of organometallic species to appropriately protected 5α, 10α-epoxy, 9 (11) -olefins, as disclosed in Teutsch et al., Steroid 37, 361 (1981), is a known chemical methodology. C11-oxo of 19-norandrost-5-ene, suitably protected according to (ao E. Ottow et al., Tetr. Lett., 5253 (1993)) as a reactive functional group for functional interconversion to C-11 aldehyde, for example. Other methods with functional groups can be used to make the claimed compounds. Of course, the two summarized methods can be combined to achieve a similar goal. A so-called Birch reduction of the aromatic counterpart of the appropriately functionalized steroid, dissolution of a metal reducing agent of Δ-4,5-9,11-dienone, or 3-keto-Δ4,5- Ketalize the steroid to introduce a double bond at the 5 (10) position. The method of ketalization directly leads to the desired Δ-5 (10) -isomer of interest, or to a mixture of ketals which can be separated by chromatography or crystallization at appropriate stages of synthesis. Careful hydrolysis of the ketal at C3 generally results in the desired 3-oxo-Δ-5 (10) -isomer, which can be converted to 3-OH compound by hydride reduction. Saturated steroids (ie, 5αH-derivatives) are readily available under reducing conditions such as dissolving alkali metals in amines or ammonia. A double bond is generally introduced at C14,15 by first introducing a double bond at the C15, C16 position and then isomerizing this bond to the C14, C15 position according to known procedures. Alternatively, double bonds introduced at C15, C16 can be used to construct additional substituents at C15, such as by adding conjugates with cyanide. Introduction of substituents on C16 can be readily accomplished by alkylation with appropriate bases and electrophiles.

In addition, the present invention relates to pharmaceutically acceptable adjuvants, as disclosed in the standard reference Gennaro et al., Remington's Pharmaceutical Science (18th ed., Mack publishing Company, 1990, in particular Part 8: Pharmaceutical Preparations and Their Manufacture.). It relates to a pharmaceutical composition comprising a steroid compound of the present invention mixed. Mixtures of steroid compounds of the present invention with pharmaceutically acceptable adjuvants may be compressed into solid dosage units such as pills, tablets, or processed into capsules or suppositories. Using pharmaceutically suitable liquids, the compounds can be applied as preparations for injection in the form of solutions, suspensions, emulsions or as nebulizers such as nasal sprays. In order to prepare dosage units such as tablets, conventional additives such as fillers, colorants, polymeric binders and the like can be used. In general, any pharmaceutically acceptable additive that does not inhibit the function of the active compound can be used. Steroid compounds of the invention can be included in implants, vaginal rings, patches, gels, and any other agent for sustained release.

Examples of suitable carriers that can be administered with the composition include lactose, starch, cellulose derivatives, and the like, or mixtures thereof used in appropriate amounts.

The invention also relates to the use of the steroid compounds of the invention in the manufacture of a medicament for use in the treatment of estrogen deficiency related diseases such as peri-menopausal and / or postmenopausal diseases. Thus, the present invention relates to the medical symptoms of postmenopausal and / or postmenopausal (menopausal) diseases and osteoporosis. That is, to a method of treatment in the field of HRT (hormonal replacement therapy) comprising administering to a patient (female) the aforementioned compound (a suitable pharmaceutical dosage form).

The present invention further relates to the use of the steroid compound of the present invention in the manufacture of a medicament having a contraceptive activity. Accordingly, the present invention relates to a method of contraception comprising administering medical instructions for contraception, ie, subjects of female or female animals, customary progestogens and estrogens customary in the art, wherein the estrogen is a Pharmaceutical dosage forms).

Finally, the present invention relates to the use of steroid compounds used in the manufacture of a medicament with selective estrogen activity, which medicament is generally suitable for the field of HRT (hormonal replacement therapy).

The amount of the steroid used is in the conventional range for estradiol derivatives, such as in the range of 0.01 to 10 mg in a single dose.

The invention is illustrated below with reference to some non-limiting examples and corresponding schemes.

Compound (3α, 11β, 17β) -11- (2-propenyl) -19-norpregone-5 (10) -ene-20-yne-3,17-diol (Compound 11) and compound (3α, 11β , 16α, 17β) -16-methyl-11- (2-propenyl) -19-norpregine-5 (10) -ene-20-yne-3,17-diol (Compound 16) is represented by Scheme 1 It is disclosed with reference to. The compounds are referred to by number. The number has the corresponding structural formula in Schemes 1-7.

compound 2

To a solution of 17.3 g of CuI and 3.84 g of LiCl in 250 mL of anhydrous THF was added 90.6 mL of a 1M allylmagnesium bromide solution in diethyl ether at -70 ° C. After stirring for an additional 20 minutes, 11.4 mL of trimethylchlorosilane was added followed by a 7.5 g solution of steroid 1 in 100 mL of THF. The reaction mixture was kept below -60 ° C throughout the reaction. After stirring for 1 h, saturated NH ₄ Cl aqueous solution was poured to quench the reaction. The product was extracted with ethyl acetate and then purified by column chromatography to give 2 6.25 g as colorless oil. NMR 5.20 (m, CH allyl); 5.0 (CH ₂ , allyl); 3.04 (m, H 11).

3

Of NaOH 800 mg sodium borohydride in 0.4 g 2 9.6 g of a mixture solution of 100 ㎖ methanol and methylene chloride containing 30 ㎖ was added at 0~5 ℃. After stirring for 1.5 hours, the reaction was terminated and the mixture was treated with 20 ml of acetone for 0.5 hours.

The reaction was then poured into water and extracted with ethyl acetate to give 3 9.5 g. NMR 3.59 (t, CHOH); 2,98 (m, H 11), 0.92 (s, CH ₃ ).

4

A 6N HCl 8 ㎖ to 3 9.5 g of the acetone solution was added 100 ㎖. After stirring for 2 hours, the mixture was neutralized with NaHCO ₃ , concentrated to a small volume, diluted with water and extracted with ethyl acetate. This gave 4 8.2 g of colorless amorphous material. NMR 5.68 (m, H 4); 3.10 (m, H 11); 3.65 (m, CHOH).

5

A 4 8.2 g solution in 100 mL of anhydrous THF was added to 500 mL of liquid NH ₃ at −70 ° C. The mixture was treated with an amount of lithium metal (about 500 mg) until the blue color of the reaction mixture was maintained for at least 15 minutes. The reaction was quenched by addition of a portion of NH ₄ Cl.

The residue remaining after evaporation of NH ₃ was diluted with water and extracted with ethyl acetate.

Chromatographic purification yielded 5 4.0 g as a colorless oil. R _f 0.55 (heptane / ethyl acetate 1/1 v / v).

NMR 2.80 (ab, CH ₂ at C4); 0.93 (s, CH ₃ ).

6

To a 5 4.0 g solution in 80 ml methanol was added 6 ml trimethylorthoformate, followed by 0.8 g toluenesulfonic acid. After stirring for 2 hours, ketalization was complete. The mixture was treated with 6 ml of pyridine and concentrated to a small volume. The residue was diluted with water and extracted with ethyl acetate. 4.7 g of residue consisted of nearly pure 6 ; tlc, R _f 0.78 (heptane / ethyl acetate 1/1, v / v).

NMR 3.22, 3.25 (2x s, OCH ₃ ).

7

6 g of molecular sieve (4A) was added to a solution of 6 33 g in 50 ml of acetone followed by 3.2 g of N-methylmorpholine-N-oxide and 150 mg of tetrapropylammonium perruthenate. The mixture was stirred for 1 hour, and 5 g of silica gel and 50 ml of heptane were sequentially added to the reaction mixture, followed by further 5 minutes of stirring. The mixture was filtered in high-flow and then partially concentrated and taken up in ethyl acetate, washed with water and concentrated. The residue was passed over a short silica column to give 7 2.9 g. R _f 0.52 (heptane / ethyl acetate 7/3). NMR 1.02 (s, CH ₃ ).

8

Lithiumacetylides were prepared from dibromoethene and butyllithium for ethynylation.

To 0.74 ml of 1,2-dibromoethene in 20 ml of THF was added 11 ml of a BuLi 1.6 M solution in hexane at -70 ° C. After stirring for 15 minutes, a solution of 7 800 mg in 2 ml THF was added. The mixture was allowed to warm to room temperature in 15 minutes, after 15 minutes more at room temperature the reaction was quenched with water and the product extracted with ethyl acetate. After concentration it was passed through a short silica column to give 8 810 mg as a white amorphous material. R _f 0.48 (heptane-ethyl acetate 7/3), R _f starting material 0.52. NMR 2.61 (s, acetylene).

9

To an 8 3.2 g suspension in 60 ml ethanol 0.16 g oxalic acid in 16 ml water was added. The mixture was stirred for 2.5 hours, gradually homogenizing. The reaction mixture was treated with NaHCO ₃ and concentrated to a small volume. Water was then added and the product extracted with ethyl acetate. The resulting crude product was passed through a short silica gel column and crystallized from diisopropyl ether to give 9 2.3 g. Mp 136 ° C. R _f 0.66 (heptane-ethyl acetate 1/1). NMR 2.78 (ab, 2, H 4); 2.61 (s, acetylene).

10, 11

1.6 g of lithium tri-t-butoxy-aluminum hydride was added to a 9 1 g solution in 12 mL of THF. After stirring for 1 hour at room temperature, the mixture was treated with water and neutralized by addition of 2N HCl. The product was extracted with ethyl acetate and chromatographed on silica gel (heptane / ethyl acetate 8/2 as eluent). As a result, 0.56 g of 3β alcohol 10 (Mp 121 to 123 ° C.) and 0.24 g of 3α alcohol 11 (Mp 84 to 87 ° C.) were obtained.

R _f 0.53 ( 10 ) and 0.45 ( 11 ), heptane / ethyl acetate 1/1. NMR (3αOH) 3.82 (m, CHOH); (3βOH) 4.08 (m, CHOH).

12

To a solution of lithium hexamethyldisilazide (prepared from 1.9 ml of 1.6M BuLi-hexane solution in 0.7 ml of dry THF and 0.71 ml of hexamethyldisilazane), 7 1 g in 5 ml of THF and 0.7 ml of DMPU were added at -40 ° C. It was. The mixture was stirred at −40 ° C. for 0.5 h and then 225 μl CH ₃ I was added by syringe. After further stirring at −40 ° C. for 0.5 hours, the reaction was terminated. The mixture was diluted with water and extracted with ethyl acetate. Thus, the chromatography of the isolated crude product gave 12 1.3 g. R _f 0.43 (heptane / ethyl acetate 8/2).

13

According to the procedure disclosed in the preparation of 8 , 12 1.3 g of 12 was converted to the required 13 to obtain 1.2 g. R _f 0.46 (heptane / ethyl acetate 7/3). R f ( 12 ) 0.55.

14

To a solution of 13 800 mg in 20 mL of ethanol was added a 80 mg solution of oxalic acid in 5 mL of water. The mixture was stirred for 1 h and then neutralized by addition of NaHCO ₃ . After dilution with water and extraction with ethyl acetate, 14 0.7 g remained as crystalline material. R _f 0.47 (heptane / ethyl acetate 7/3).

15,16

130 mg of sodium borohydride was added to a solution of 14 725 mg in 20 ml of a mixture of ethanol and THF 1/1. After stirring for 1 hour, 2 ml of acetone was added to remove some excess reagent. After 15 minutes, the mixture was poured into water and the product extracted with ethyl acetate. The material thus obtained was purified by chromatography on silica gel using methylene chloride-acetone or hexane-ethyl acetate as eluent. This obtained 300 mg of 16 (3α-OH) and 75 mg of 15 (3β-OH). R _f ( 15 ) 0.47 (methylene chloride / acetone 95/5). Rf ( 16 ) 0.54 (methylene chloride / acetone 95/5).

Example 2

Synthesis of compound (3β, 5α, 11β, 17β) -11-difluoromethyl-19-norpregine-20-yn-3,17-diol (Compound 21) is described with reference to Scheme 2.

18

To a 4 g solution of a known aldehyde 17 in 200 ml of methylene chloride was added 10 ml of dimethylsulfurtrifluoride. The mixture was stirred at room temperature for 48 hours, poured into ice water, extracted with methylene chloride and washed with NaHCO ₃ . After concentration and chromatography (SiO ₂ -heptane-ethyl acetate 2/1), 18 2.5 g were obtained. Mp 138-139. Double triplet of 6.05 ppm CHF ₂ NMR (CDCl ₃ ); 5.9 s, H 4; 0.95 (s, CH ₃ ).

19

The acetylene gas was passed at 0 ° C. for 45 minutes through 1.3 g of potassium-t-butoxide and 18 1 g of a degassed mixture in 7 ml THF and 2 ml t-butanol. The mixture was poured into water and extracted with ethyl acetate. After washing and concentration, the residual material was treated with diisopropyl ether to give 19 0.85 g as white solid. Mp 178-180. R _f 0.43 (heptane-ethyl acetate 1/1).

20

To a solution of 20 mg Li in 10 ml liquid NH ₃ was added a solution of 19 300 mg in 6 ml THF at −60 ° C. After stirring for 1 minute, the mixture was treated with 0.5 g of NH ₄ Cl. NH ₃ was evaporated and the residue was treated with water and extracted with ethyl acetate. The material thus obtained was purified by chromatography to give 20 140 mg. Mp 224-225, R _f 0.64 (heptane-ethyl acetate 7/3).

21

To a 25 mg solution of LiAlH _{4 in} 4 ml THF was added 20 85 mg in 1 ml THF at −60 ° C. After stirring for 5 minutes, the mixture was quickly warmed to RT and prepared by adding 45 μl of water, 45 μl of 3N NaOH solution and 140 μl of water. The precipitate was filtered off and the filtrate was taken up in ethyl acetate and washed with 2N HCl and water. The residue remaining after drying and concentration was triturated with diisopropyl ether to give 21 50 mg. Mp 168-169 ° C., R _f 0.30 (toluene-ethyl acetate 7/3) NMR 3.6 ppm CHOH, 2.65 CH acetylene, 6.0 double triplet CHF ₂ ).

Example 3

Compound (3β, 5α, 11β, 17β) -11- (2-fluoroethyl) -19-norpregine-20-phosphor-3,17-diol (Compound 31) and Compound (3α, 5α, 11β, 17β Synthesis of) -11- (2-fluoroethyl) -19-norpregine-20-phosphor-3,17-diol (Compound 32) is described with reference to Scheme 3.

23

To a 4.95 g solution of 11β-hydroxyethylestrone-3-methylether ( 22 ) in 115 mL of THF, 66 g of molecular sieve 4A and 45 mL of 1M TBAF in THF (anhydrous) were added followed by 5.3 g of tosylfluoride. . The mixture was stirred and refluxed for 2 hours. The reaction was then cooled and poured into 700 mL of 10% NaHCO ₃ aqueous solution and extracted with ethyl acetate. After concentration of the solvent and chromatography, 3.4 g of 23 was isolated. R _f 0.39 (heptane / ethyl acetate 7/3).

24

A 23 4 g solution in a mixture of 30 mL THF and 30 mL methanol was treated with 0.1 mL 4N NaOH and 0.23 g NaBH ₄ . After stirring for 1 hour, the reaction was poured into water and extracted with ethyl acetate. The crude material was filtered through a short silo column to yield 24 3.8 g. R _f 0.26 (heptane / ethyl acetate 7/3) R _f 23 : 0.33.

25

To a solution of 24 3.8 g in a mixture of 40 mL THF and 230 mL liquid NH ₃ was added 5 g of Li at −33 ° C. The mixture was stirred for 5 hours. Treatment with 45 ml of ethanol removed excess lithium. Ammonia was evaporated and the residue was diluted with water and extracted with ethyl acetate. Upon drying and concentration, 3.7 g of crude 1,2,5 (10) dienolether was obtained. It was dissolved in 30 ml of acetone, and 3 ml of 6N HCl was added thereto. After stirring for 3 hours the mixture was neutralized with NaHCO ₃ , diluted with water and extracted with ethyl acetate to give 25 2.8 g. R _f 0.10 (heptane / ethyl acetate 4/6).

26

A 25 0.84 g solution in a mixture of 30 mL of liquid NH ₃ and 6 mL of THF was treated with a small piece of lithium at −60 ° C. until the blue color of the reaction mixture lasted at least 5 minutes. Excess reagent was removed by addition of a small amount of NH ₄ Cl and the NH ₃ was evaporated. The residual material was diluted with water and extracted with ethyl acetate. The solvent was concentrated to give 0.80 g of nearly pure material. R _f (0.39 (heptane / ethyl acetate 1/1), R _f 25 , 0.24.

27

To a solution of 26 0.8 g in 8 ml dichloromethane was added 2.8 ml ethylene glycol, 2.5 ml triethylorthoformate and 5 mg toluenesulfonic acid. The mixture was stirred overnight, poured into saturated NaHCO ₃ solution and extracted with ethyl acetate. The crude material thus obtained was purified by passing through a short silica gel column to give 27 0.72 g. R _f 0.46 (heptane / ethyl acetate 1/1), R _f 26 , 0.38.

28

To a solution of 27 0.72 g in 15 ml of acetone were added 1 g of molecular sieve (4A), 0.70 g of N-methylmorpholine-N-oxide and 30 mg of tetrapropylammonium perruthenate. The mixture was stirred for 1 hour. 1 g of silica gel and 15 ml of heptane were added to the reaction mixture in order, followed by further stirring for 5 minutes. The mixture was filtered on high-flow, concentrated to some extent and taken up in ethyl acetate, washed with water and then concentrated. The residue was passed through a short silica column to give 28 0.59 g. R _f 0.62 (heptane / ethyl acetate 1/1).

29

Lithiumacetylides were prepared from dibromoethene and butyllithium for ethynylation.

To 0.74 ml of 1,2-dibromoethene in 20 ml of THF was added 11 ml of a BuLi 1.6 M solution in hexane at -70 ° C. After stirring for 15 minutes, a solution of 28 590 mg in 2 mL THF was added. The mixture was allowed to warm to room temperature in 15 minutes, after 15 minutes more at room temperature the reaction was quenched with water and the product extracted with ethyl acetate. After concentration it was passed through a short silica gel column to give 29 430 mg as a white amorphous material. R _f 0.11 (heptane-acetone 9/1), R _f starting material 0.21.

30

1 mL of 2N HCl was added to a solution of 29 0.43 g in 15 mL of acetone. The mixture was stirred for 2 hours, treated with saturated aqueous NaHCO ₃ solution and extracted with ethyl acetate to give 0.40 g of substantially pure 30 . R _f 0.18 (heptane / ethyl acetate 7/3). R _f 29 : 0.23.

31/32

30 mg sodium borohydride was added to a solution of 30 0.40 g in 4 mL THF and 4 mL ethanol. After stirring for 0.5 hour, a few drops of acetone were added to decompose the excess reagent. After stirring for 15 minutes, the reaction was poured into water and extracted with ethyl acetate. Thus, the obtained crude material was subjected to column chromatography to obtain 80 mg of 3αOH isomer 32 and 160 mg of 3βOH derivative 31 . R _f 31 : 0.37, R _f 32 ; 0.42, R _f starting material 0.48 (heptane / acetone 6/4).

Example 4

Compound (3α, 11β, 17β) -11- (3-butenyl) -19-norpregine-5 (10) -ene-20-yne-3,17-diol (compound 42) and (3β, 11β, Synthesis of 17β) -11- (3-butenyl) -19-norpregine-5 (10) -ene-20- phosphorus-3,17-diol (Compound 43) is described with reference to Scheme 4.

33

A 55 g solution of steroid 1 in a mixture of 300 mL THF and 300 mL methanol was treated with a 2.7 g solution of sodium borohydride (containing 3 mg NaOH) in 30 mL water. After stirring for 1 hour, the reduction was completed and 75 ml of acetone was added to remove excess hydride. After stirring for an additional hour the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was concentrated to give 33 54 g. R _f 0.31 (heptane / ethyl acetate 4/6), R _f starting material 0.42.

34

To a solution of 33 54 g in 350 ml DMF was added 35 g of imidazole followed by 37 ml of trimethylsilyl chloride at −10 ° C. After further stirring for 0.5 hours, the reaction was terminated. The mixture was poured into 1.5 L of water and extracted with ether. The residue obtained after concentration of the organic material was triturated with 80% aqueous ethanol to give 50 g of pure 34 . Mp 90-91 ° C., R _f 0.79 (heptane / ethyl acetate 4/6), R _f starting material 0.36.

35

100 mg of CuJ was added at -10 ° C to a butenyl magnesium bromide solution prepared from 0.51 ml of 4-bromo-1-butene and 119 mg of Mg in 20 ml of THF. After stirring for 0.5 h, the mixture was cooled to -30 < 0 > C and 34 1 g in 5 ml of THF were added. The reaction mixture was brought to room temperature in about 1 hour. Then, 100 ml of saturated NH ₄ Cl aqueous solution was added, followed by extraction with ethyl acetate. Chromatography yielded 35 0.9 g. R _f 0.54 (heptane / ethyl acetate 6/4), R _f starting material 0.60.

36

To a solution of 35 8.65 g in 80 ml acetone 2 ml 2N HCl was added. The mixture was stirred for 2 hours and then neutralized with saturated aqueous NaHCO ₃ solution, concentrated to a small volume, diluted with water and extracted with ethyl acetate. Therefore, by passing the crude material so obtained in a short silica gel column to give a 36 5.3 g; R _f 0.18 (heptane / ethyl acetate 7/3), R _f starting material 0.51.

37

Lithium metal scrap was added to a solution of 36 5.3 g in a mixture of 340 ml of liquid NH ₃ , 110 ml of THF and 9 ml of t-butanol at −70 ° C. until blue remained for 45 min (± 350 mg). The addition of NH ₄ Cl eliminated excess reagent. Ammonia was evaporated and the residue was diluted with water and extracted with ethyl acetate. The crude material thus obtained was passed through a short silica gel column to give 3.8 g of 37 ; R _f 0.46 (heptane / ethyl acetate 6/4), R _f starting material 0.22.

38

To a 3.3 g solution of 37 in 60 ml of methanol 5 ml of trimethylorthoformate and 0.3 g of p-toluenesulfonic acid were added. After stirring for 1 hour at room temperature, 1 ml of pyridine was added to neutralize the mixture. The mixture was concentrated to one third of the initial volume, poured into water and extracted with ethyl acetate to give 38 3.7 g after chromatographic purification. R _f 0.60 (heptane / ethyl acetate 1/1), R _f starting material 0.48.

39

To a 3.7 g solution of 38 in 45 ml of acetone, molecular sieve (4A) was added followed by 3.6 g of N-methylmorpholine-N-oxide and 100 mg of tetrapropylammonium perruthenate. The mixture was stirred for 1 hour. 5 g of silica gel was added to the reaction mixture, followed by 100 ml of heptane, and the mixture was further stirred for 5 minutes. The mixture was filtered over high-flow, partially concentrated and taken up in ethyl acetate, washed with water and concentrated. The residue was passed through a short silica column to give 39 3.3 g. R _f 0.51 (heptane / ethyl acetate 7/3), starting material R _f 0.38.

40

Lithiumacetylides were prepared from dibromoethene and butyllithium for ethynylation.

To 0.74 ml of 1,2-dibromoethene in 20 ml of THF was added 11 ml of a BuLi 1.6 M solution in hexane at -70 ° C. After stirring for 15 minutes, a solution of 39 0.8 g in 2 ml THF was added. The mixture was allowed to warm to room temperature in 15 minutes, after 15 minutes more at room temperature the reaction was quenched with water and the product extracted with ethyl acetate. After concentration it was passed through a short silica gel column to give 40 0.96 g as a white amorphous material. R _f 0.15 (heptane-acetone 95/5), R _f starting material 0.30.

41

To a solution of 40 0.95 g in 20 mL of ethanol was added 0.6 g of oxalic acid in 3 mL of water. The mixture was stirred for 1.5 h. The reaction mixture was treated with NaHCO ₃ and concentrated to a small volume. Water was added and the product extracted with ethyl acetate. The crude product thus separated was passed through a short silica gel column to give 41 0.55 g. R _f 0.33 (heptane / ethyl acetate 7/3), R _f starting material 0.40.

42/43

30 mg of sodium borohydride was added to a solution of 41 0.55 g in 4 mL of THF and 4 mL of ethanol. After stirring for 0.5 hour, a few drops of acetone were added to decompose the excess reagent. After stirring for 15 more minutes, the reaction was poured into water and extracted with ethyl acetate, and the resulting crude material was column chromatographed to give 90 mg of 3αOH isomer 42 (Mp 159 ° C.) and 150 mg of 3βOH derivative 41 . Mp 90 ° C. R _f 41 : 0.31, R _f 42 ; 0.23, R _f starting 0.41 (heptane / ethyl acetate 6/4).

Example 5

Compound (3β, 7α, 11β, 17β) -11- (2-fluoroethyl) -7-methyl-19-norpregine-5 (10) -ene-20-yne-3,17-diol (Compound 54 ) And compound (3α, 7α, 11β, 17β) -11- (2-fluoroethyl) -7-methyl-19-norpregone-5 (10) -ene-20-yne-3,17-diol ( The synthesis of compound 55) is described with reference to Scheme 5.

45

The addition of trimethyl orthoformate in 12 ㎖ 44 4g solution in methanol 35 ㎖, followed by adding toluene sulfonic acid 0.3 g. After stirring for 1 hour the starting material was consumed and the reaction mixture was neutralized and concentrated by the addition of 1 g of NaHCO ₃ . The residue was diluted with water and extracted with ethyl acetate. Chromatography of the crude material gave 45 3.4 g. R _f 0.61 (heptane / ethyl acetate 7/3), R _f starting material 0.35.

46

0.5 g of NaOH was added to a 45 3.4 g solution in 50 ml of methanol. Stir for 2 hours and then complete the saponification reaction. The mixture was concentrated, diluted with water and extracted with ethyl acetate to give 46 3 g as colorless oil. R _f 0.31 (heptane / ethyl acetate 7/3), R _f starting material 0.65.

47

To a 3.6 g solution of 46 in 30 ml of DMF was added 2.8 g of imidazole followed by 2 g of t-butyldimethylsilyl chloride. After stirring for 2 hours, the mixture was poured into water and extracted with ethyl acetate. The crude material was passed over a short silica gel column to give 3.8 g of 47 . R _f 0.70 (heptane / ethyl acetate 7/3), R _f starting material 0.61.

48

A 9-BBN solution was prepared from 1.75 ml of 1,5-cyclooctadiene and 1.4 ml of borane-dimethylsulfide complex in 40 ml of THF. To this was added 3.8 g of 47 in 5 ml of THF. The mixture was stirred for 2 hours and then quenched by the careful addition of water (5 mL) followed by the addition of 10 mL 2N NaOH and 8 mL 30% H ₂ O ₂ . After vigorously stirring for 2 hours, the reaction mixture was further diluted with water, extracted with ethyl acetate and washed with 10% Na ₂ SO ₃ aqueous solution. During concentration and chromatography, 48 2,8 g was isolated. R _f 0.27 (heptane / ethyl acetate 7/3), R _f starting material 0.70.

49

A mixture of 48 g and 48 g of tosyl chloride in 5 ml of pyridine was stirred at 0-5 ° C. for 5 hours. Then 1 ml of water was added and stirred for 15 minutes. The reaction mixture was further diluted with water and extracted with ethyl acetate and the crude product was purified by chromatography to give 49 1.1 g. Mp 120 ° C., R _f 0.57 (heptane / ethyl acetate 7/3), R _f starting material 0.30.

50

A solution of 49 400 mg in 5 ml of anhydrous 1M TBAF in THF was stirred for 5 hours to induce silyl functional degradation with fluoride formation. The mixture was poured into water and extracted with ethyl acetate. Purification by chromatography gave 50 185 mg. Mp 161-162 ° C., R _f 0.35 (heptane / ethyl acetate 7/3), R _f starting material 0.53.

51

To a solution of 50 180 mg in 5 ml of acetone was added molecular sieve (4A) followed by 200 mg of N-methylmorpholine-N-oxide and 10 mg of tetrapropylammonium perruthenate. The mixture was stirred for 1 hour. 0.5 g of silica gel was added to the reaction mixture, followed by 10 ml of heptane, and further stirred for 5 minutes. The mixture was filtered over high-flow, partially concentrated and taken up in ethyl acetate, washed with water and concentrated to give 51 150 mg. Mp 166 ° C. R _f 0.45 (heptane / ethyl acetate 7/3), R _f starting material 0.35.

52

Lithiumacetylides were prepared from dibromoethene and butyllithium for ethynylation.

To 0.30 mL of 1,2-dibromoethene in 6 mL of THF was added 4.5 mL of a BuLi 1.6 M solution in hexane at -70 ° C. After stirring for 15 minutes, a 50 150 mg solution in 1 ml THF was added. The mixture was allowed to warm to room temperature in 15 minutes, after 15 minutes more at room temperature the reaction was quenched with water and the product extracted with ethyl acetate. Concentrated and treated with some heptane to give 52 140 mg as a white solid. Mp 168 ° C. R _f 0.38 (heptane-acetone 95/5), R _f starting material 0.40.

53

To a solution of 52 145 mg in 3 ml of ethanol and 1.5 ml of THF was added 0.2 g of oxalic acid in 3 ml of water. The mixture was stirred for 1.5 hours. The reaction mixture was treated with NaHCO ₃ and concentrated to a small volume. Water was added and the product extracted with ethyl acetate. The crude product thus separated was passed through a short silica gel column to give 53 125 mg. R _f 0.23 (heptane / ethyl acetate 7/3), R _f starting material 0.38.

54/55

20 mg of sodium borohydride was added to a solution of 53 125 mg in 2 ml THF and 1 ml ethanol. After 0.5 hour, the reduction reaction was completed. The mixture was diluted with water and extracted with ethyl acetate. The crude product thus separated was purified by passing through a reversed-phase C-18 column using acetonitrile-water as eluent to give 40 mg 3αOH 55 and 20 mg 3βOH 54 as amorphous materials having the same R _f value on silica gel. . R _f 0.43 (CH ₂ Cl ₂ / acetone 9/1), R _f starting material 0.70.

Example 6

Compounds of this Example were prepared according to Scheme 6.

57

A solution of 80 mg of sodium borohydride and 112 mg of sodium hydroxide in 12 ml of methanol was prepared at 7 ° C. in a mixture of 18 ml of methanol and 4 ml of methylene dichloride at 0 ° C., 7α, 11β-dimethylester-4-ene-3,17-dione ( 56). ) Was added dropwise to the solution. After stirring for 1 hour, 12 ml of acetone was added to remove the excess boron hydride, followed by stirring for 15 minutes. The mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed once with saturated NaCl solution, dried, concentrated and purified on a silica column to give 57 0.74 g contaminated with some 3,17-diol. (3,17-diol was removed in the next step); R _f 0.40 (heptane / ethyl acetate 6/4), NMR (CDCl ₃ ) δ 3.60 (t, 1, 17 α H), 0.77 (d, ₃ , 7 α CH ₃ ), 1.08 (d, 3, 11 β CH ₃ ).

58

0.2 g of p-toluenesulfonic acid was added to a solution of 57 0.74 g in 15 mL methanol and 1.1 mL trimethylorthoformate. The mixture was stirred for 2 hours. 0.1 ml of pyridine was added and poured into water. The product was extracted with ethyl acetate and purified by chromatography on silica using heptane / ethyl acetate as eluent to afford 0.59 g of 3,3-dimethylketal 58 . R _f 0.47 (heptane / ethyl acetate 6/4); NMR δ3.20 (2s, 6, OCH ₃ ), 3.65 (t, 1, 17αH), 0.86 (s, 3, 18CH ₃ ), 0.77 (d, 3, 7αCH ₃ ), 0.90 (d, 3, 11βCH ₃ ).

59

To 0.59 g of steroid 58 in 10 ml of acetone, 0.6 g of N-methylmorpholine-N-oxide and 40 mg of tetrapropylammonium perruthenate were added successively. After stirring for 1 hour, 10 ml of heptane and 1 g of silica were added. The mixture was stirred for 15 minutes and then filtered on celite and concentrated and the residue passed through a short column of silica to give a 59 0.56 g; R _f 0.55 (heptane / ethyl acetate 6/4); NMR δ 0.98 (s, 3, 18CH ₃ ), 0.82 (d, 3, 7αCH ₃ ), 0.92 (d, 3, 11βCH ₃ ), 3.20 ( ₂ × s, 6, OCH ₃ ).

60

Lithium hexamethyldisilazide was prepared by adding 1.24 ml of a 1.55 M BuLi-hexane solution at −40 ° C. to a 0.44 ml solution of bistrimethylsilylamine in 4 ml of THF. After stirring for 1/2 hour, a solution of 0.56 g 59 and DM6 0.46 mL in 8 mL THF was added. Stirring was continued for 45 min at -40 < 0 > C, then 140 [mu] l of methyl iodide was added. Stirred another 30 minutes to complete alkylation. The mixture was poured into 40 ml of saturated NH ₄ Cl solution and extracted with ethyl acetate. Chromatographic purification yielded 0.55 g of 16α-methylated product 60 . R _f 0.73 (heptane / ethyl acetate 1/1); Starting material R _f 0.69; NMR δ1.11 (d, 3, 16αCH ₃ ), 1.02 (s, 3, 18CH ₃ ), 0.82 (d, 3, 7αCH ₃ ), 0.91 (d, 3, 11βCH ₃ ).

61

Lithium acetylide was prepared by adding a 9.5 mL solution of 1.55M BuLi-hexane at 0.60 mL to 1,20 di-bromoethane in 20 mL THF. After stirring for 1/2 hour, a 0.55 g solution of ketone 60 in 2 mL of THF was added and the cooling device was removed so that the mixture was gradually warmed to room temperature. Water was added and the product was extracted with ethyl acetate. After chromatographic purification to give a 61 0.50 g. R _f 0.22 (heptane / ethyl acetate 9/1); Starting material R _f 0.42; NMR δ 1.18 (d, 3, 16αCH ₃ ), 1.02 (s, 3, 18CH ₃ ), 0.78 (d, 3, 7αCH ₃ ), 0.94 (d, 3, 11βCH ₃ ), 2.66 (s, 1, acetylene ).

62

To a 0.49 g solution of 61 in 20 mL of ethanol was added 50 mg of oxalic acid in 3 mL of water. The mixture was stirred for 4 hours. The reaction mixture was treated with 5% aqueous sodium bicarbonate solution and the product was extracted with ethyl acetate and passed through a silica column to remove some impurities to give 63 250 mg; R _f 0.40 (heptane / ethyl acetate 6/4); Starting material R _f 0.49; NMR δ 2.80 (m, 2, H 4), 1.19 (d, 3, 16 α CH ₃ ), 1.04 (s, 3, 18 CH ₃ ), 0.82 (d, 3, 7 α CH ₃ ), 0.93 (d, 3, 11 β CH ₃₎ ), 2.67 (s, 1, acetylene).

63/64

THF 5 ㎖ of lithium in 62 240 ㎎ solution (t- butoxy) ₃ AlH was added to 360 ㎎. The mixture was stirred for 1 h, then poured into water and the product extracted with ethyl acetate. The isomeric alcohol thus obtained was separated by preparative PHLC (reverse phase C18) using an acetonitrile / water gradient. The product obtained after concentration of the eluent was crystallized from water-ethanol. This gave 68 mg of 3α-hydroxy derivative 64 and 70 mg of 3β-isomer 63 . _{R f (63/64) 0.36} ( heptane / ethyl acetate 6/4), starting material R _f 0.54. Mp ( 63 ) 165-167 ° C, Mp ( 64 ) 171-172 ° C. NMR ( 64 ) δ3.80 (m, 1, H3), 2.67 (s, 1, acetylene), 1.17 (d, 3,16αCH ₃ ), 1.02 (s, 3,18CH ₃ ), 0.77 (d, 3, 7αCH ₃ ), 0.90 (d, 3,11βCH ₃ ). NMR ( 63 ) δ4.05 (m, 1, H3), 2.67 (s, 1, acetylene), 1.18 (d, 3,16αCH ₃ ), 1.02 (s, 3,18CH ₃ ), 0.77 (d, 3, 7αCH ₃ ), 0.93 (d, 3,11βCH ₃ ).

Example 7

Compounds of this Example were prepared according to Scheme 7.

66

To a 10 g solution of 11α-hydroxynordienedione ( 65 ) in 45 ml of DMF was added 10 g of imidazole, and 8.6 ml of trimethylsilyl chloride was added at 0 ° C. After stirring for 1 hour, the mixture was poured into iced water and the product extracted with ethyl acetate. Chromatography of the crude crushing, and then with heptane to give 66 7.8 g 11- trimethylsilyloxy derivative. Mp 89-90 degreeC. NMR δ 4.08 (m, 1, 11αH), 5.80 (s, 1H, H 4), 6.25 (m, 2, H 6, 7), 0.15 (s, 9, trimethylsilyl).

67

To a solution of 66 5.3 g of 66 and 20 mg of Cu (Oac) _{2 in} 20 mL of THF, 9.8 mL of 1M methylmagnesium chloride in THF was added dropwise at -30 ° C. The mixture was stirred for 1 hour, poured into a 6 mL solution of concentrated sulfuric acid in 300 mL of water and stirred overnight. The product was extracted with ethyl acetate, dried and concentrated to give 4.8 g of solid material sufficiently pure for further reaction. NMR δ 5.85 (s, 1, H 4), 3.92 (m, 1, H 11 α), 0.83 (d, 3, 7 α CH ₃ ), 0.95 (s, 3, 18 CH ₃ ); R _f 0.22 (heptane / ethyl acetate 7/3), starting material R _f 0.65.

68

To a solution of 4.8 g of 67 and 6.6 g of NMO in 100 ml of acetone were added 130 mg of tetrapropylammonium perruthenate. After stirring for 2 hours, 2 g of silica gel and 100 ml were added. The mixture was further stirred for 1/2 hour and filtered over celite. The filtrate was concentrated and the residue was treated with diisopropyl ether to give 4 g of nearly pure Trion 68 . NMR δ 5.89 (s, 1, H 4), 0.89 (s, 3, 18 CH ₃ ), 0.92 (d, 3, 7 α CH ₃ ); R _f 0.46 (heptane / ethyl acetate 7/3), starting material R _f 0.24.

69

A mixture of 3.5 g of steroid 67 , 1.3 ml of ethanedithiol, 300 mg of p-toluenesulfonic acid and 35 ml of ethanol was refluxed for 1 hour. The reaction was cooled to rt and 80 mL of cold 1/2 N NaOH was added. After stirring for 1 hour, the product was filtered off and washed with cold water. After drying in vacuo at 50 ° C., 69 4.6 g were obtained; NMR δ5.66 (s, 1, H4), 3.22 and 3.38 (m, 4, thioketal), 0.85 (s, 3, 18CH ₃ ), 0.88 (d, 3, 7αCH ₃ ); R _f 0.88 (toluene / acetate 7/3), starting material R _f 0.59.

70

A small portion of 450 mg of NaBH ₄ was added at −20 ° C. to a solution of 69 4.0 g in 100 ml methanol and 50 ml methylene chloride. After further stirring for 1 hour, the reduction was terminated and the reaction was treated with 5 ml of acetone and then concentrated to a small volume, diluted with 100 ml of water and extracted with methylene chloride. After drying and concentration, 3.9 g of nearly pure 70 were obtained: NMR δ 3.90 ((m, 1, 17 α H), 0.82 (d, 3, 7 α CH ₃ ), 0.73 (s, 3, 18 CH ₃ ); R _f 0.39 ( Heptane / ethylacetate 1/1), starting material R _f 0.65.

71

A 2.5 mL solution of trimethylsilyl chloride in 20 mL ether was added dropwise at 0 ° C. to a mixture of 70 4.7 g in 70 mL DMF and 2.6 g imidazole. After stirring for 1 hour, the reaction was diluted with ice water and the product was extracted with ethyl acetate. After drying and concentration of the organic phase, the residue was triturated in an ice bath with 80% aqueous ethanol, filtered and dried in vacuo at 50 ° C. to give 71 5.2 g; NMR δ 3.76 (t, 1, 17 α H), 0.65 (s, 3, 18 CH ₃ ), 0.80 (d, 3, 7 α CH ₃ ), 5.60 (s, 1, H 4); R _f 0.86 (heptane / ethyl acetate 1/1), starting material R _f 0.37.

73

A suspension of 4.4 g potassium t-butoxide and 16.2 g methyltriphenylphosphonium bromide in 130 ml of toluene was heated at 100 ° C. for 1/2 hour under a nitrogen atmosphere. The yellow mixture was cooled to 50 ° C. and a 4.6 g solution of steroid 71 in 20 ml of toluene was added. The reaction was further stirred at 100 ° C. for 1 hour, cooled and poured into 500 ml of ice water. The product was extracted with toluene, washed, dried and concentrated. The residue was chromatographed on toluene / silica gel to remove most reagent contaminants. The crude 72 (6.3 g) thus obtained was dissolved in 20 mL THF and 18 mL solution of 1 M TBAF in THF was added. After stirring for 1/2 hour, the mixture was diluted with water and extracted with ethyl acetate. Purification of the thus obtained product to chromatography to obtain 73 4.7 g. Mp 177-180 ° C .; NMR δ 4.77 and 4.86 (AB, 2, methylene H's), 5.60 (s, 1, H4), 3.72 (m, 1, 17αH), 0.70 (s, 3, 18CH ₃ ), 0.77 (d, 3, 7αCH ₃ ); R _f 0.10 (heptane / ethyl acetate 9/1), starting material R _f 0.73.

74

A 2.45 g solution of periodic acid in a 12 mL water and 12 mL methanol mixture was added to a 73 4.7 g solution in 40 mL of methylene chloride. The mixture was stirred for 45 minutes and then diluted with water. The product was extracted with methylene chloride. The organic layer was washed several times with 5% aqueous sodium thiosulfate solution and water, then dried and concentrated. The residue was purified by column chromatography on silica gel to give 74 2.6 g; NMR δ 0.73 (s, 3, 18CH ₃ ), 0.79 (d, 3, 7αCH ₃ ), 5.88 (s, 1, H4), 4.83, 4.94 (AB, 2, methylene H's), 3.78 (m, 1, 17αH); R _f 0.25 (heptane / ethyl acetate 6/4), starting material R _f 0.48.

75

A reaction of talc was monitored while stirring a mixture of 74 2.6 g, 7 ml of trimethylorthoformate, 480 mg of p-toluenesulfonic acid and 50 ml of methanol at room temperature. After 2.5 hours, the reaction was poured into saturated aqueous NaHCO ₃ and extracted with ethyl acetate. After drying in vacuo and concentration, 3.1 g of a 1/1 mixture of Δ5,6 and Δ5 (10) ketals were obtained; R _f 0.46 (heptane / ethyl acetate 6/4) Starting material R _f 0.25; NMR (1: 1 mixture of ketals) δ3.15, 3.22, 3.24 (s, 6, OCH ₃ signal), 0.77, 0.87 (2x d, 3, 7αCH ₃ ), 0.65, 0.71 (2x s, 3, 18CH ₃ ).

76

The crude product 75 was dissolved in 60 ml of acetone. To this was added 3.7 g of N-methylmorpholine-N-oxide and 75 mg of tetrapropylammonium perruthenate. The mixture was stirred for 2 hours, then 1 g of silica gel and 60 ml of heptane were added. After stirring for 15 minutes, the reaction was filtered over celite and the filtrate was concentrated to dryness. The residue was passed through a short silica column to give 1.9 g of ketone 76 as a mixture of Δ5 (10) and Δ5,6 ketals. NMR conventional signals δ 0.82, 0.93 (2xd, 3, 7αCH ₃ ), 0.79, 0.85 (2xs, 3, 18CH ₃ ), 3.15, 3.22, 3.25 (signal of s, 6, OCH ₃ ), 4.70, 4.85 and 4.87 and 4.93 (2xAB, 2, methylene H's); R _f 0.58 (heptane / ethyl acetate 6/4), starting material R _f 0.45.

77

A solution of 76 500 mg in 10 ml THF and 0.4 ml DMPU was added dropwise at −40 ° C. to a 1.6 ml solution of 1M Li-hexamethyldisilazide in 10 ml THF. After stirring for another 45 minutes, 120 μl of methyl iodide was added. After continued stirring at −20 ° C., the reaction was poured into water and the product extracted with ethyl acetate. The material obtained after washing, drying and concentration of the organic phase was passed through a silica column to give 510 mg of 16 α-methyl derivative 77 as a double bond isomer mixture; R _f 0.56 (heptane / ethyl acetate 7/3), starting material R _f 0.48. NMR δ 1.15, 1.17 ( ₂ × d, 16αCH ₃ ).

78

Li-acetylide was prepared by dropwise addition of 7.1 ml of 1.6M BuLi-hexane to 0.46 ml of 1,2-dibromoethane in 10 ml of THF at -60 ° C. After stirring for 1/2 hour, a 500 mg solution of 10 mL THF 10 mg heavy steroid 77 was added and the reaction mixture was stirred for 1/2 hour, during which time the temperature was raised to room temperature. Then water was added and the product extracted with ethyl acetate. The material thus obtained was passed through a short silica column to give 78 540 mg as a double bond isomer mixture. NMR δ2.74 and 2.76 (2xs, 1, acetylene), 1.17, 1.19 (2xd, 3, 16αCH ₃ ), 0.78, 0.88 (2xd, 3, 7αCH ₃ ); R _f 0.50 (heptane / ethyl acetate 7/3), starting material R _f 0.60.

79

To a solution of 78 440 mg in 20 ml acetone 4 ml 4N HCl was added. After stirring for 1 hour, the reaction was terminated and the mixture was poured into saturated aqueous NaHCO ₃ and extracted with ethyl acetate. After washing, drying and concentration, an almost pure 78 380 mg was obtained, which was used directly in the next step. NMR δ 5.88 (s, 1, H4), 5.90 (AB, 2, methylene), 2.76 (s, 1, acetylene), 1.18 (d, 3, 16αCH ₃ ), 0.88 (s, 3, 18CH ₃ ), 0.79 (d, 3, 7αCH ₃ ).

80

A small piece of Li foil was added to a solution of 79 280 mg in a mixture of 30 mL of liquid NH ₃ and 10 mL of THF at −40 ° C. until blue lasted 15 minutes. Solid NH ₄ Cl was then added to quickly quench the slight excess of Li and evaporate the ammonia. To the residue was added 100 ml of water and the mixture was extracted with ethyl acetate. The separated organic material after washing, drying and concentration contained nearly pure 80 ; R _f 0.57 (heptane / ethyl acetate 6/4), NMR δ 4.78, 4.88 (AB, 2, methylene), 2.66 (s, 1, acetylene), 1.19 (d, 3, 16αCH ₃ ), 0.86 (s, 3, 18CH ₃ ), 0.90 (d, 3, 7αCH ₃ ).

81

To a solution of 80 160 mg in 10 ml THF, a small portion of LiAlH ₄ was added at 0 ° C. until the reduction was complete. Then 0.1 mL of saturated aqueous Na ₂ SO ₄ was added followed by some solid Na ₂ SO ₄ . The mixture was stirred for 15 minutes and then filtered over celite. The filtrate was concentrated, acetonitrile-water was used as the eluent, and the residue was purified through a preparative HPLC column packed with reversed phase C-18 silica to give 81 55 mg. Mp 198-199 ° C .; R _f 0.33 (heptane / ethyl acetate 6/4), starting material 0.57. NMR δ 3.67 (m, 1, 3αH), 4.70, 4.82 (AB, 2, methylene), 2.65 (s, 1, acetylene), 1.18 (d, 3, 16αCH ₃ ), 0.83 (s, 3, 18CH ₃ ), 0.89 (d, 3, 7αCH ₃ ).

Example 8

Compounds are tested for estrogen receptor activity in binding assays and transactivation assays.

Determination of competitive binding to cytoplasmic human estrogen receptor in the cell-derived rec.CHO is estradiol (E ₂₎ and compared to estrogen present in the cytosol of transfected stably with the human estrogen receptor a recombinant Chinese hamster ovary (CHO) cells It is used to evaluate the relative affinity (ratio of efficacy) of the test compound to the receptor. Cytosols were prepared from recombinant CHO cells stably transfected with human estrogen receptor. This cell line was created in the field of biotechnology and biochemistry (BBC) (N. V. organanon) and is known under the name CHO-ER (2B1). Reference compounds are ethynylestradiol and estriol.

The antiestrogenic activity of the compounds was achieved using recombinant Chinese hamster ovary (CHO) stably cotransfected with human estrogen receptor α (hERα) or β receptor (hERβ), rat oxytocin promoter (RO) and luciferase reporter gene (LUC). Measured by in vitro bioassay. Antiestrogenic Activity of Test Compounds That Inhibit Transactivation of Enzyme Luciferase Mediated Through Estrogen Receptor by Estrogen Org2317 (Estradiol, 1,3,5 (10) -Estratriene-3,17β-diol) Ratio) to standard Org 34790 (ICI 164.384; (7α, 17β) -N-butyl-3,17-dihydroxy-N-methylestra-1,3,5 (10) -triene-7-undecaneamide ).

Test Medium: Intact recombinant CHO cells were stably cotransfected with human estrogen receptor, rat oxytocin promoter and luciferase reporter genes. The cell line was created in the field of biotechnology and biochemistry (BBC) (N. V. organganone) and is known under the name CHO-ERRO 2B1-1E9.

The results are shown in Table 1 below.

Data is expressed as a percentage of the action of the reference compound in the analysis.

compound α-bond α-transactivation β-bond β-transactivation 11 57 58 1.1 0.8 15 35 27 0.3 0.3 21 8.6 7.7 0.2 0.1 31 37 9.6 0.1 0.2 32 2.6 2.4 <0.1 0.1 42 29 2 0.1 <0.04 43 11.9 1.3 0.1 <0.1 54 27.5 29.7 0.1 1.0 55 36 61.5 0.1 1.9 63 25 22 0.4 0.1 64 35 29 0.2 0.2 81 n.t.r. 27 n.t.r. 0.1 n.t.r .: No test results available.

Claims (5)

Non-aromatic estrogen steroids satisfying Formula I: Formula I Where R ¹ is H, (C ₁ -C ₃ ) alkyl or (C ₂ -C ₃ ) acyl; R ² is H, α- (C ₁ -C ₄ ) alkyl, α- (C ₂ -C ₄ ) alkenyl or α- (C ₂ -C ₄ ) alkynyl; R ³ is H or (C ₁ -C ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl or (C ₂ -C ₄ ) alkynyl at the 15 or 16 position of the steroid backbone, respectively; R ⁴ is H or (C ₁ -C ₅ ) alkyl, (C ₂ -C ₅ ) alkenyl or (C ₂ -C ₅ ) alkynyl, each optionally substituted with halogen; Preferably ethynyl; R ⁵ is H, (C ₁ -C ₃ ) alkyl or (C ₂ -C ₃ ) acyl; R ⁶ is (C ₁ -C ₅ ) alkyl, (C ₂ -C ₅ ) alkenyl, (C ₂ -C ₅ ) alkynyl or (C optionally substituted with halogen or (C ₁ -C ₃ ) alkyloxy, respectively ₁ -C ₅ ) alkylidene; Dotted lines indicate optional double bonds. A non-aromatic estrogen steroid according to claim 1 which satisfies Formula II: Formula II Where R ¹ is H, (C ₁ -C ₃ ) alkyl or (C ₂ -C ₃ ) acyl; R ² is H, α- (C ₁ -C ₄ ) alkyl, α- (C ₂ -C ₄ ) alkenyl or α- (C ₂ -C ₄ ) alkynyl; R ³ is H or (C ₁ -C ₄ ) alkyl at position 16 of the steroid backbone; R ⁴ is ethynyl; R ⁵ is H, (C ₁ -C ₃ ) alkyl or (C ₂ -C ₃ ) acyl; R ⁶ is (C ₁ -C ₅ ) alkyl, (C ₂ -C ₅ ) alkenyl, (C ₂ -C ₅ ) alkynyl, which may be substituted with chlorine or fluorine, respectively. The method of claim 2, R ¹ is H; R ² is H; R ³ is H, 16α-methyl or 16α-ethyl; R ⁴ is ethynyl; R ⁵ is H; A non-aromatic estrogen steroid characterized by R ⁶ being propenyl, allyl or butenyl. A pharmaceutical composition comprising the steroid compound according to any one of claims 1 to 3 and a pharmaceutically acceptable adjuvant. Use of the steroid compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of estrogen deficiency dependent disease.